Novel solution- and solid-phase chemistry of α-sulfonated ketones applicable to combinatorial chemistry [21]

Full text of DOI:10.1021/ja002768p

10246
J. Am. Chem. Soc. 2000, 122, 10246-10248
Table 1. Loading of R-Sulfonated Ketones onto Polystyrene
Sulfonic Acid Resin 8 from Olefins/Epoxides in One Pota
Novel Solution- and Solid-Phase Chemistry of
r-Sulfonated Ketones Applicable to Combinatorial
Chemistry
K. C. Nicolaou,* Phil S. Baran, and Yong-Li Zhong
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037
Department of Chemistry and Biochemistry
UniVersity of California, San Diego
9500 Gilman DriVe, La Jolla, California 92093
ReceiVed July 27, 2000
In our continuing search for enabling technologies for cascade
and combinatorial synthesis, we identified the R-sulfonated
ketone1 as a rather unexplored chemical entity with considerable
potential in organic synthesis. Particularly enticing was the
prospect of loading an organic substrate onto a solid support
through a leaving group linker.2 By tapping into the rich chemistry
of the related R-halo ketones3 and by developing chemistry
exclusive to R-sulfonated ketones,4 we envisaged a unique strategy
wherein the essence of new diversity could be introduced at the
cleavage step (I f II, Figure 1). Of utmost importance was the
development of a new and efficient synthesis of these systems
from readily available materials. In this work we report the
realization of such a scenario utilizing a novel one-pot synthesis
of R-sulfonated ketones from olefins, both in solution and on solid
phase, and leading to a fast-track entry into a wide ranging variety
of structural types.
a Reagents and conditions: olefin (2.5 equiv), DMDO (4.0 equiv,
∼0.1 M solution in acetone), CH2Cl2, 1 h, 25 °C; then resin 8 (1.0
equiv, based on ∼1.0 mmol/g loading), 4 h, 25 °C; then NaHCO3 (6.0
equiv), DMP (2.0 equiv), 25 °C, 12 h. b Based on yield of R-hydroxy-
ketone obtained after treatment with K2CO3/H2O/THF (see Scheme 2
for conditions, resin loading ∼1.0 mmol/g) and observed mass gain.
c 2:1 mixture of regioisomers obtained after basic cleavage.
Figure 1. Mechanistic rationale for the “heterocycle-release” strategy.
DMDO-mediated5 (for abbreviations of reagents, see Scheme
footnotes) epoxidation in the same pot] with p-TsOH in CH2Cl2
at room temperature, gradual conversion to the R-hydroxy tosylate
was observed. Addition of DMP6 led cleanly to the R-tosyloxy
ketone 2 in 65% isolated yield after flash chromatography (silica,
hexane:Et2O (2:1)). This protocol was considerably simplified and
After considerable experimentation we found that by treating
cyclooctene oxide [Scheme 1, derived from cyclooctene 1 by
(1) Previous syntheses of R-sulfonated ketones: (a) via SO3-mediated
nitrosation of olefins: Zefirov, N. S.; Zyk, N. V.; Lapin, Y. A.; Nesterov, E.
E.; Ugrak, B. I. J. Org. Chem. 1995, 60, 6771. (b) From ketones using
hypervalent iodine reagents: Tuncay, A.; Dustman, J. A.; Fisher, G.; Tuncay,
C. I.; Suslick, K. S. Tetrahedron Lett. 1992, 33, 7647; Lodaya, J. S.; Koser,
G. F. J. Org. Chem. 1988, 53, 210. (c) From enol ethers using hypervalent
iodine reagents: Moriarty, R. M.; Epa, W. R.; Penmasta, R.; Awasthi, A. K.
Tetrahedron Lett. 1989, 30, 667. (d) From enol esters, enol ethers, and
enamines using arylsulfonyl peroxides: Hoffman, R. V.; Carr, S. C.;
Jankowski, B. C. J. Org. Chem. 1985, 50, 5148.
(2) For related sulfonate linkers, see: Hunt, J. A.; Roush, W. R. J. Am.
Chem. Soc. 1996, 118, 9998; Rueter, J. K.; Nortey, S. O.; Baxter, E. W.;
Leo, G. C.; Reitz, A. B. Tetrahedron Lett. 1998, 975; Baxter E. W.; Rueter,
J. K.; Nortey, S. O.; Reitz, A. B. Tetrahedron Lett. 1998, 979. For a recent
extensive review on linking and cleavage technology in solid-phase organic
synthesis, see: Guillier, F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100,
2091. See also: Bra¨se, S.; Dahmen, S. Chem. Eur. J. 2000, 6, 1899.
(3) Verhe, R.; De Kimpe, N. In The Chemistry of Functional Groups,
Supplement D; Patai, S., Rappoport, Z., Eds.; John Wiley and Sons: London,
1983; p 813.
(4) (a) Photochemical reactions of R-tosyloxy and R-methanesulfonyloxy
ketones: Charlton, J. L.; Lai, H. K.; Lypka, G. N., Can. J. Chem. 1980, 58,
458. (b) Addition of methoxide and amines to R-nosyloxy ketones: Hoffman,
R. V.; Jankowski, B. C.; Carr, C. S.; Duesler, E. N. J. Org. Chem. 1986, 51,
130.
(5) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847.
(6) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Dess,
D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (c) Meyer, S. D.;
Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
10.1021/ja002768p CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/28/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 41, 2000 10247
Scheme 1. One-Pot Entry to R-Tosyloxy Ketones from
generalized (Table 1) by synthesizing the immobilized variant of
p-TsOH7 (8) and using it to load a series of olefinic substrates as
R-sulfonated ketones via the one-pot procedure described above
and summarized in Scheme 1 and Table 1. Cis- and trans-olefins
(entry 5) are loaded onto the solid support with equal efficiency.
The R-sulfonated ketones are remarkably stable chemical entities,
both in solution and on solid phase.
Olefinsa
Having at our disposal a variety of R-sulfonated ketones, we
proceeded to utilize an array of new and classical chemical
reactions to implement the unique functionalizing-cleavage
stratagem alluded to above (Figure 1). In this regard the carbonyl
group which stabilizes the sulfonate moiety adjacent to it was
also expected to activate it upon being attacked by a nucleophile.8
As depicted in Schemes 1 and 2, we found that R-sulfonated
ketones could be dismantled in solution or excised from the solid
support, with concurrent formation of a variety of novel molecular
frameworks. Thus, treatment of 2 with methanolic K2CO3 led to
the isolation of R-methoxy-ketone 6 in 83% isolated yield
(Scheme 1) while release of 20 occurred with similar efficiency
from solid-bound 11 (81%, Scheme 2).9 Photolytic cleavage of 2
led to the R,â-unsaturated ketone 5 in 65% isolated yield (Scheme
1) and photorelease of 27 occurred in 82% isolated yield from
11 (Scheme 2).10 Application of our recently disclosed protocol11
for oxidation adjacent to the carbonyl group furnished unsaturated
ketone 4 in 72% isolated yield (Scheme 1). We were delighted
a Reagents and conditions: (a) DMDO (1.3 equiv, ∼0.1 M solution
in acetone), CH2Cl2, 1 h, 25 °C; then p-TsOH (5.0 equiv), 12 h, 25 °C,
then NaHCO3 (6.0 equiv), DMP (2.0 equiv), 25 °C, 65%; (b) 2-aminothio-
phenol (10 equiv), PPTS (cat.), benzene, reflux (Dean-Stark), 24 h, 82%;
(c) IBX (2.0 equiv every 5 h), p-TsOH (cat.), DMSO:fluorobenzene (10:
1), 85 °C, 15 h, 63%; (d) benzene (0.05 M), hanovia (450 W, medium
pressure Hg lamp), 8 h, 65%; (e) K2CO3 (5.0 equiv), MeOH, 25 °C, 1 h,
83%, DMDO ) dimethyldioxirane, p-TsOH ) p-toluenesulfonic acid,
DMP ) Dess-Martin periodinane, PPTS ) pyridinium p-toluene-
sulfonate, IBX ) o-iodoxybenzoic acid, DMSO ) dimethyl sulfoxide.
Scheme 2. Twenty Functionalizing-Cleavage Options for Use with the R-Sulfonated Ketone Resin 11a
a Reagents and conditions: (a) 2-iodobenzoic acid (10 equiv), Et3N (5.0 equiv), toluene, reflux (Dean-Stark), 16 h, 78%; (b) K2CO3 (1.0 equiv),
THF/H2O (1:1), reflux, 30 min, 95%; (c) 1,2-diaminobenzene (10 equiv), PPTS (cat.), toluene, reflux (Dean-Stark), 16 h, 85%; (d) 1,2-benzenedithiol
(10 equiv), PPTS (cat.), benzene, reflux, 16 h, 50% 18 + ∼50% of endocyclic olefin (cis/trans mixture); (e) ethylacetoacetate (10 equiv), methylamine
(10 equiv, 40% solution in H2O), toluene, 60 °C, 24 h, 83%; (f) for 20: K2CO3 (5.0 equiv), MeOH, 25 °C, 8 h, 95%; (g) for 21: same as for 20, then
AcOH, 25 °C, 5 h, 95%; (h) 2-iodophenol (10 equiv), Et3N (5.0 equiv), toluene, 90 °C, 8 h, 95%; (i) 2-amino-5-methylphenol (B) (10 equiv), PPTS
(cat.), benzene, reflux (Dean-Stark), 24 h, 58%; (j) for 24: ethylene glycol/benzene (1:1), PPTS (cat.), 90 °C, 12 h, 63%; for 25: 2-mercaptoethanol
(10 equiv), PPTS (cat.), benzene, reflux (Dean-Stark), 16 h, 88%; (k) 4-methylesculetin (C) (10 equiv), PPTS (cat.), benzene/DMSO (10:1), 85 °C, 24
h, 38%; (l) benzene, hanovia (450 W, medium pressure, Hg lamp), 45 °C, 6 h, 82%; (m) morpholine (5.0 equiv), CH2Cl2, 25 °C, 12 h, 95%; (n)
thioacetamide (10 equiv), PPTS (cat.), benzene, reflux (Dean-Stark), 36 h, 83%; (o) 2-aminopyridine (5.0 equiv), benzene, reflux, 16 h, 89%; (p)
thiophenol (5.0 equiv), benzene, reflux, 12 h, 95%; (q) 1,2-diamino cyclohexane (10 equiv, cis/trans), PPTS (cat.) benzene, reflux (Dean-Stark), 24 h,
60%; (r) ethanolamine (10 equiv), PPTS (cat.), benzene, reflux (Dean-Stark), 36 h, 60%; (s) 2-aminothiophenol (A) (10 equiv), PPTS (cat.), benzene,
reflux (Dean-Stark), 24 h, 87%. b Formed via the labile, but detectable, methoxy-epoxide intermediate, see Supporting Information.

10248 J. Am. Chem. Soc., Vol. 122, No. 41, 2000
Communications to the Editor
to observe efficient conversion of 2 to the novel heterocycle 3
simply upon condensation with 2-aminothiophenol (A) (benzene,
Dean-Stark trap, reflux, cat. PPTS, 82% isolated yield, Scheme
1). Heterocycle 34 cleanly departed from the solid support (87%
yield) following treatment of 11 with A under similar conditions
(Scheme 2).
can be easily removed, thus potentially facilitating high-throughput
applications of this method.
Finally, a range of nucleophiles were employed to elicit useful
functionalizing-cleavage events resulting in a variety of R-sub-
stituted ketones (Scheme 2). Thus, upon treatment of conjugate
11 with mild aqueous base (catalytic K2CO3, THF:H2O (2:1)),
cleavage ensued to furnish the R-hydroxy ketone (16). Formation
of R-amino ketones 28 and 30 was accomplished using morpho-
line and 2-aminopyridine, respectively.4b Phenols, carboxylic
acids, and thiols were also found to be viable nucleophiles in
this reaction. Thus products 22, 15, and 31 were obtained upon
treatment of resin 11 with 2-iodophenol, 2-iodobenzoic acid, and
thiophenol, respectively.
In conclusion, we have explored the chemistry of the R-sul-
fonated ketone moiety and proven its versatility in the construction
of molecular diversity including novel heterocycles. The reactions
reported herein perform equally well in solution and on solid
support. The solid-phase version, in particular, provides both a
novel linking forum for ketones and a new concept for extensive
and wide ranging diversity introduction via cleavage from the
resin (heterocycle-release), enabling combinatorial chemistry and
key building-block construction. Carbon nucleophiles also enter
these reactions (unpublished results).
This “heterocycle-release” strategy (see Figure 1) was tested
repeatedly and delivered a range of ubiquitous13 heterocyclic
systems (Scheme 2). Thus, derivatives of both the dioxane (24,
26) and morpholine (33) ring systems were released from the
resin simply by heating with ethylene glycol, 4-methylesculetin
(C), or 1-amino-2-hydroxy ethylene in benzene, respectively. The
fused thiazole 29 was constructed by heating 11 with excess
thioacetamide, while treatment with 1,2-dithiobenzene or 2-mer-
captoethanol led to the thianthrene derivative 18 and the 1,4-
oxathiene 25, respectively.12a Pyrazines 17 and 32 were fabricated
simply by reaction with 1,2-diamino benzene and 1,2-diamino
cyclohexane (cis/trans mixture), respectively. Access to the
phenoxazine derivative 23 from 11 was accomplished using
2-amino-5-methylphenol (B). Treatment of 11 with ethyl aceto-
acetate and methylamine furnished the tetrasubstituted pyrrole 19
in 85% yield.12b To the best of our knowledge,14 the direct
synthesis of heterocycles such as 17, 18, 23, 24, 32-34 from
R-halo or sulfonated ketones is unprecedented.15 Using a polymer-
bound isocyanate (Aldrich) or liquid-liquid extraction, excess
reagents
Acknowledgment. We thank Jeff Pfefferkorn for advice on the
synthesis of the sulfonic acid resin 8. We also thank Drs. D. H. Huang
and G. Siuzdak for NMR spectroscopic and mass spectrometric assistance,
respectively. This work was financially supported by the Skaggs Institute
for Chemical Biology, the National Institutes of Health (U.S.A.), a
predoctoral fellowship from the National Science Foundation (P.S.B),
and grants from Pfizer, Glaxo, Merck, Schering Plough, Hoffmann-La
Roche, Boehringer Ingelheim, DuPont, Abbott Laboratories, and Novartis.
(7) Nicolaou, K. C.; Snyder, S. A.; Bigot, A.; Pfefferkorn, J. A. Angew.
Chem., Int. Ed. 2000, 39, 1093; Smith, K.; Hou, D. J., J. Org. Chem. 1996,
61, 1530.
(8) This hypothesis is supported by the observations reported in ref 4b and
the isolation of an epoxide intermediate en route to compounds 20 and 21
(Scheme 2, see Supporting Information for spectral data).
(9) These compounds (6, 20, 21) arise from the corresponding labile
methoxy epoxides. See Supporting Information for spectral data. See also ref
4b for related studies.
(10) For a discussion of the mechanism of this reaction and its use on a
steroidal substrate, see: Iwasaki, S.; Schaffner, K. HelV. Chim. Acta 1968,
51, 557.
(11) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000,
122, 7596.
Supporting Information Available: Full characterization for new
compounds and experimental procedures (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA002768P
(14) Literature search using SciFinder Scholar; see also: Joule, J. A.; Mills,
K.; Smith, G. F. Heterocyclic Chemistry, 3rd ed.; Chapman & Hall: New
York, 1995.
(15) According to a recent SciFinder Scholar search, benzothiazines,
phenoxazines, pyrazines, and derivatives thereof are valuable small-molecule
leads for a plethora of uses including antifungal, antiinflammatory, antitumor,
anti-HIV, antimicrobial, CNS disorders, and potassium channel openers.
(12) (a) Thiazoles from R-halo ketones: Schwarz, G. Organic Syntheses;
Wiley & Sons; New York, 1955; Collect. Vol. III, p 332. (b) Pyrroles from
R-halo ketones: Roomi, M. W.; MacDonald, S. F. Can. J. Chem. 1970, 48,
1689.
(13) Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39, 2887.